The characterization of abnormal proteins responsible for genetic disorders affecting the nervous system permits the isolation of normal cDNA and genomic DNA that can be used to correct inherited protein deficiencies using gene therapy. Particularly suited for initial attempts at gene therapy are those disorders (such as Gaucher disease, the most common sphingolipidosis) in which the systemic and neurologic manifestations of the disorder are the consequence of abnormalities of bone marrow derived cells, like the macrophage. In these instances the transfer of normal genes to either specific tissue or bone marrow progenitor or stem cells is a rationale therapeutic approach. Using the lysosomal disorder Gaucher disease as a model, we utilize retroviral vectors to transfer and express human glucocerebrosidase in mouse and Gaucher patient cell lines. Other strategies being investigated include receptor mediated gene transfer, transplantation of neuroprogenitor cells, and the use of neo-organs consisting of recombinantly altered cells acting as depots of protein production. The initial goal of this research is the application of gene therapy to non-neuronopathic phenotypes. Transgenic animal models are developed using homologous recombination in embryonic stem cells to generate mouse models of human disease. When our understanding of the pathogenetic mechanisms of inherited neurologic and psychiatric diseases improves and as retroviral-mediated expression of genes in specific tissues and cells becomes more predictable, we can extend the use of gene therapy to treatment of selected disorders affecting the nervous system.